Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease

ABSTRACT

A method of treating and preventing secondary hyperparathyroidism in CKD by increasing or maintaining blood concentrations of both 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in a patient by administering 25-hydroxyvitamin D 3  with or without 25-hydroxyvitamin D 2  and, as necessary, 1,25-dihydroxyvitamin D 2  as a Vitamin D hormone replacement therapy.

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of U.S. patent application Ser. No. 12/597,234filed Dec. 4, 2009, which is the National Phase of InternationalApplication No. PCT/US2008/61594 filed Apr. 25, 2008, which claims thebenefit of priority under 35 U.S.C. §119(e) of U.S. Provisional PatentApplication Ser. No. 60/913,850 filed Apr. 25, 2007. The disclosure ofeach priority application is incorporated herein by reference.

BACKGROUND

Secondary hyperparathyroidism is a disorder which develops primarilybecause of Vitamin D deficiency. It is characterized by abnormallyelevated blood levels of parathyroid hormone (PTH) and, in the absenceof early detection and treatment, it becomes associated with parathyroidgland hyperplasia and a constellation of metabolic bone diseases. It isa common complication of chronic kidney disease (CKD), with risingincidence as CKD progresses. Secondary hyperparathyroidism can alsodevelop in individuals with healthy kidneys, due to environmental,cultural or dietary factors which prevent adequate Vitamin D supply.

“Vitamin D” is a term that refers broadly to the organic substancesnamed Vitamin D₂, Vitamin D₃, Vitamin D₄, etc., and to their metabolitesand hormonal forms that influence calcium and phosphorus homeostasis.“Vitamin D deficiency” is a term that broadly refers to reduced or lowblood levels of Vitamin D, as defined immediately above.

The most widely recognized forms of Vitamin D are Vitamin D₂(ergocalciferol) and Vitamin D₃ (cholecalciferol). Vitamin D₂ isproduced in plants from ergosterol during sunlight exposure and ispresent, to a limited extent, in the human diet. Vitamin D₃ is generatedfrom 7-dehydrocholesterol in human skin during exposure to sunlight andalso is found, to a greater extent than Vitamin D₂, in the human diet,principally in dairy products (milk and butter), brain, certain fish andfish oils, and egg yolk. Vitamin D supplements for human use consist ofeither Vitamin D₂ or Vitamin D₃.

Both Vitamin D₂ and Vitamin D₃ are metabolized into prohormones by oneor more enzymes located in the liver. The involved enzymes aremitochondrial and microsomal cytochrome P450 (CYP) isoforms, includingCYP27A1, CYP2R1, CYP3A4, CYP2J3 and possibly others. These enzymesmetabolize Vitamin D₂ into two prohormones known as 25-hydroxyvitamin D₂and 24(S)-hydroxyvitamin D₂, and Vitamin D₃ into a prohormone known as25-hydroxyvitamin D₃. The two 25-hydroxylated prohormones are moreprominent in the blood, and are separately or collectively referred toas “25-hydroxyvitamin D”. Vitamin D₂ and Vitamin D₃ can be metabolizedinto these same prohormones outside of the liver in certain epithelialcells, such as enterocytes, which contain the same (or similar) enzymes,but extrahepatic prohormone production probably contributes little toblood levels of 25-hydroxyvitamin D.

The rates of hepatic and extrahepatic production of the Vitamin Dprohormones are not tightly regulated, and they vary mainly withintracellular concentrations of the precursors (Vitamin D₂ and VitaminD₃). Higher concentrations of either precursor increase prohormoneproduction, while lower concentrations decrease production. Hepaticproduction of prohormones is inhibited by high levels of25-hydroxyvitamin D via a poorly understood mechanism apparentlydirected to prevention of excessive blood prohormone levels. However,there is little evidence of feedback regulation of extrahepaticprohormone production.

The Vitamin D prohormones are further metabolized in the kidneys intopotent hormones by an enzyme known as CYP27B1 (or 25-hydroxyvitaminD₃-1α-hydroxylase) located in the proximal kidney tubule. Theprohormones 25-hydroxyvitamin D₂ and 24(S)-hydroxyvitamin D₂ aremetabolized into hormones known as 1α,25-dihydroxyvitamin D₂ and1α,24(S)-dihydroxyvitamin D₂. Likewise, 25-hydroxyvitamin D₃ ismetabolized into a hormone known as 1α,25-dihydroxyvitamin D₃ (orcalcitriol). These hormones are secreted by the kidneys into the bloodfor systemic delivery. The two 25-hydroxylated hormones, usually farmore prominent in the blood than 1α,24(S)-dihydroxyvitamin D₂, areseparately or collectively referred to as “1,25-dihydroxyvitamin D”.Vitamin D prohormones can be metabolized into hormones outside of thekidneys in keratinocytes, lung epithelial cells, enterocytes, cells ofthe immune system (e.g., macrophages) and certain other cells containingCYP27B1 or similar enzymes, but such extrarenal hormone production isincapable of sustaining normal blood levels of 1,25-dihydroxyvitamin Din advanced CKD. Extrarenal hormone production permits intracellularconcentrations of 1,25-dihydroxyvitamin D to exceed and be independentof blood levels of 1,25-dihydroxyvitamin D.

Blood levels of 1,25-dihydroxyvitamin D are precisely regulated by afeedback mechanism which involves PTH. The renal 1α-hydroxylase (orCYP27B1) is stimulated by PTH and inhibited by 1,25-dihydroxyvitamin D.When blood levels of 1,25-dihydroxyvitamin D fall, the parathyroidglands sense this change via intracellular Vitamin D receptors (VDR) andsecrete PTH. The secreted PTH stimulates expression of renal CYP27B1and, thereby, increases production of Vitamin D hormones. As bloodconcentrations of 1,25-dihydroxyvitamin D rise again, the parathyroidglands attenuate further PTH secretion. As blood PTH levels fall, renalproduction of Vitamin D hormones decreases. Rising blood levels of1,25-dihydroxyvitamin D also directly inhibit further Vitamin D hormoneproduction by CYP27B1. PTH secretion can be abnormally suppressed insituations where blood 1,25-dihydroxyvitamin D concentrations becomeexcessively elevated, as can occur in certain disorders or more commonlyas a result of bolus (usually intravenous) doses of Vitamin D hormonereplacement therapies. Oversuppression of PTH secretion can cause orexacerbate disturbances in calcium homeostasis and has been linked tovascular calcification. The parathyroid glands and the renal CYP27B1 areso sensitive to changes in blood concentrations of Vitamin D hormonesthat serum 1,25-dihydroxyvitamin D is tightly controlled, fluctuating upor down by less than 20% during any 24-hour period. In contrast to renalproduction of Vitamin D hormones, extrarenal production is not underprecise feedback control.

The Vitamin D hormones have essential roles in human health which aremediated by the intracellular VDR. In particular, the Vitamin D hormonesregulate blood calcium levels by controlling intestinal absorption ofdietary calcium and reabsorption of calcium by the kidneys. The VitaminD hormones also participate in the regulation of cellulardifferentiation and growth and normal bone formation and metabolism.Further, Vitamin D hormones are required for the normal functioning ofthe musculoskeletal, immune and renin-angiotensin systems. Numerousother roles for Vitamin D hormones are being postulated and elucidated,based on the documented presence of intracellular VDR in nearly everyhuman tissue.

The actions of Vitamin D hormones on specific tissues depend on thedegree to which they bind to (or occupy) the intracellular VDR in thosetissues. The three Vitamin D hormones specifically discussed herein havenearly identical affinities for the VDR and, therefore, have essentiallyequivalent VDR binding when present at the same intracellularconcentrations. VDR binding increases as the intracellularconcentrations of the hormones rise, and decreases as the intracellularconcentrations fall. Intracellular concentrations of the Vitamin Dhormones change in direct proportion to changes in blood hormoneconcentrations with the exception that in cells containing CYP27B1 (orsimilar enzymes), intracellular concentrations of the Vitamin D hormonesalso change in direct proportion to changes in blood and/orintracellular prohormone concentrations, as discussed above. In suchcells, adequate intracellular prohormone concentrations can preventreductions in intracellular 1,25-dihydroxyvitamin D concentrations dueto low blood levels of 1,25-diydroxyvitamin D.

Vitamin D₂, Vitamin D₃ and their prohormonal forms have affinities forthe VDR which are estimated to be at least 100-fold lower than those ofthe Vitamin D hormones. As a consequence, physiological concentrationsof these hormone precursors exert little, if any, biological actionswithout prior metabolism to Vitamin D hormones. However,supraphysiological levels of these hormone precursors, especially theprohormones, in the range of 10 to 1,000 fold higher than normal, cansufficiently occupy the VDR and exert actions like the Vitamin Dhormones.

Blood levels of Vitamin D₂ and Vitamin D₃ are normally present atstable, concentrations in human blood, given a sustained, adequatesupply of Vitamin D from sunlight exposure and an unsupplemented diet.Slight, if any, increases in blood Vitamin D levels occur after mealssince unsupplemented diets have low Vitamin D content, even thosecontaining foods fortified with Vitamin D. The Vitamin D content of thehuman diet is so low that the National Institutes of Health (NIH)cautions “it can be difficult to obtain enough Vitamin D from naturalfood sources” [NIH, Office of Dietary Supplements, Dietary SupplementFact Sheet: Vitamin D (2005)]. Almost all human Vitamin D supply comesfrom fortified foods, exposure to sunlight or from dietary supplements,with the last source becoming increasingly important. Blood Vitamin Dlevels rise only gradually, if at all, after sunlight exposure sincecutaneous 7-dehydrocholesterol is modified by UV radiation topre-Vitamin D₃ which undergoes thermal conversion in the skin to VitaminD₃ over a period of several days before circulating in the blood.

Blood Vitamin D hormone concentrations also remain generally constantthrough the day in healthy individuals, but can vary significantly overlonger periods of time in response to seasonal changes in sunlightexposure or sustained alterations in Vitamin D intake. Markeddifferences in normal Vitamin D hormone levels are commonly observedbetween healthy individuals, with some individuals having stableconcentrations as low as approximately 20 pg/mL and others as high asapproximately 70 pg/mL. Due to this wide normal range, medicalprofessionals have difficulty interpreting isolated laboratorydeterminations of serum total 1,25-dihydroxyvitamin D; a value of 25pg/mL may represent a normal value for one individual or a relativedeficiency in another.

Transiently low blood levels of 1,25-dihydroxyvitamin D stimulate theparathyroid glands to secrete PTH for brief periods ending when normalblood Vitamin D hormone levels are restored. In contrast, chronicallylow blood levels of 1,25-dihydroxyvitamin D continuously stimulate theparathyroid glands to secrete PTH, resulting in a disorder known assecondary hyperparathyroidism. Chronically low hormone levels alsodecrease intestinal calcium absorption, leading to reduced blood calciumconcentrations (hypocalcemia) which further stimulate PTH secretion.Continuously stimulated parathyroid glands become increasinglyhyperplastic and eventually develop resistance to regulation by VitaminD hormones. Without early detection and treatment, followed byconsistent maintenance or preventative therapy, secondaryhyperparathyroidism progressively increases in severity, causingdebilitating metabolic bone diseases, including osteoporosis and renalosteodystrophy. Appropriate prophylactive therapy for early stage CKDcan delay or prevent the development of secondary hyperparathyroidism.

Chronically low blood levels of 1,25-dihydroxyvitamin D develop whenthere is insufficient renal CYP27B1 to produce the required supply ofVitamin D hormones, a situation which commonly arises in CKD. Theactivity of renal CYP27B1 declines as the Glomerular Filtration Rate(GFR) falls below approximately 60 ml/min/1.73 m² due to the loss offunctioning nephrons. In end-stage renal disease (ESRD), when thekidneys fail completely and hemodialysis is required for survival, renalCYP27B1 often becomes altogether absent. Any remaining CYP27B1 isgreatly inhibited by elevated serum phosphorous (hyperphosphatemia)caused by inadequate renal excretion of dietary phosphorous.

Chronically low blood levels of 1,25-dihydroxyvitamin also developbecause of a deficiency of Vitamin D prohormones, since renal hormoneproduction cannot proceed without the required precursors. Prohormoneproduction declines markedly when cholecalciferol and ergocalciferol arein short supply, a condition often described in the medical literatureby terms such as “Vitamin D insufficiency”, “Vitamin D deficiency” or“hypovitaminosis D”. Therefore, measurement of prohormone (serum total25-hydroxyvitamin D) levels in blood has become the accepted methodamong healthcare professionals to monitor Vitamin D status. Recentstudies have documented that the great majority of CKD patients have lowblood levels of 25-hydroxyvitamin D, and that the prevalence of VitaminD insufficiency and deficiency increases as CKD progresses.

It follows that individuals most vulnerable to developing chronicallylow blood levels of 1,25-dihydroxyvitamin D are those with CKD. Most CKDpatients typically have decreased levels of renal CYP27B1 and a shortageof 25-hydroxyvitamin D prohormones. Not surprisingly, most CKD patientsdevelop secondary hyperparathyroidism. Unfortunately, early detectionand treatment of secondary hyperparathyroidism in CKD is rare, let aloneprevention.

The National Kidney Foundation (NKF) has recently focused the medicalcommunity's attention on the need for early detection and treatment ofsecondary hyperparathyroidism by publishing Kidney Disease OutcomesQuality Initiative (K/DOQI) Clinical Practice Guidelines for BoneMetabolism and Disease in Chronic Kidney Disease [Am. J. Kidney Dis.42:S1-S202, 2003)]. The K/DOQI Guidelines identified the primaryetiology of secondary hyperparathyroidism as chronically low bloodlevels of 1,25-dihydroxyvitamin and recommended regular screening in CKDStages 3 through 5 for elevated blood PTH levels relative tostage-specific PTH target ranges, which for Stage 3 is 35-70 pg/mL(equivalent to 3.85-7.7 pmol/L), for Stage 4 is 70-110 pg/mL (equivalentto 7.7-12.1 pmol/L), and for Stage 5 is 150-300 pg/mL (equivalent to16.5-33.0 pmol/L) (defined in K/DOQI Guideline No. 1). In the event thatscreening revealed an iPTH value to be above the ranges targeted for CKDStages 3 and 4, the Guidelines recommended a follow-up evaluation ofserum total 25-hydroxyvitamin D to detect possible Vitamin Dinsufficiency or deficiency. If 25-hydroxyvitamin D below 30 ng/mL wasobserved, the recommended intervention was Vitamin D repletion therapyusing orally administered ergocalciferol. If 25-hydroxyvitamin D above30 ng/mL was observed, the recommended intervention was Vitamin Dhormone replacement therapy using oral or intravenous Vitamin D hormonesor analogs.

Current Vitamin D hormone replacement therapies available for use in CKDpatients contain 1,25-dihydroxyvitamin D₃, 19-nor-1,25-dihdroxyvitaminD₂, or 1-alpha-hydroxyvitamin D₂ and are formulated for quick orimmediate release in the gastrointestinal tract or for bolus intravenousadministration. When administered at chronically high doses (usually0.25 to 2.0 mcg orally, or 1.0 to 10 mcg intravenously), as is usuallyrequired for adequate hormone replacement, these products caneffectively restore serum total 1,25-dihydroxyvitamin D to levels above20 pg/mL and lower iPTH by at least 30% in the majority of patients.However, they cannot be administered in high enough doses to controlelevated iPTH in all patients and they sporadically cause side effects,including hypercalcemia, hyperphosphatemia, hyercalciuria andoversuppression of iPTH, in a significant minority of the patients.Health care professionals are cautious in raising the dose of thesehormone replacement therapies for purposes of improving the control ofsecondary hyperparathyroidism in patients with excessive iPTH levels dueto the increasing risk of causing such side effects.

As explained above, all CKD patients eventually develop decreased levelsof renal CYP27B1 as kidney insufficiency becomes more severe, making iteven more difficult, and eventually impossible, to treat secondaryhyperparathyroidism with Vitamin D repletion therapies alone. The safeand effective use of Vitamin D hormone replacement therapies, therefore,is essential in the later stages of CKD.

Clearly, a novel alternative approach to Vitamin D hormone replacementfor the treatment and prevention of secondary hyperparathyroidism in CKDStages 3-5 is sorely needed, in view of the problems encountered withthe currently available oral and intravenous Vitamin D hormonetherapies.

BRIEF DESCRIPTION OF THE INVENTION

In one aspect the present invention provides a method of treating andpreventing secondary hyperparathyroidism in CKD by increasing ormaintaining blood concentrations of both 25-hydroxyvitamin D and1,25-dihydroxyvitamin D in a patient by administering 25-hydroxyvitaminD₃ with or without 25-hydroxyvitamin D₂ and, as necessary,1,25-dihydroxyvitamin D₂ as a Vitamin D hormone replacement therapy. Theblood concentrations of 25-hydroxyvitamin D are increased to andmaintained at or above 30 ng/mL, with 25-hydroxyvitamin D₃ being thepredominant hormone, and blood concentrations of serum total1,25-dihydroxyvitamin D₂ are increased to or maintained within apatient's normal historical physiological range for serum total1,25-dihydroxyvitamin D without causing side effects, includinghypercalcemia, hyperphosphatemia, hypercalciuria and oversuppression ofiPTH, in a significant minority of the patients.

In another aspect, the invention provides a method of concurrentlylowering or maintaining plasma iPTH levels, increasing or maintainingserum calcium levels, maintaining serum phosphorous levels, increasingor maintaining serum 25-hydroxyvitamin D, or increasing or maintainingserum 1,25-dihydroxyvitamin D levels in a human patient by administeringto the early stage CKD patient, 25-hydroxyvitamin D₃ with or without25-hydroxyvitamin D₂ and, as necessary, 1,25-dihydroxyvitamin D₂, sothat the blood concentrations of 25-hydroxyvitamin D are increased toand maintained at or above 30 ng/mL, with 25-hydoxyvitamin D₃ being thepredominant hormone, and blood concentrations of 1,25-dihydroxyvitamin Dare increased to or maintained within a patient's normal historicalphysiological range for 1,25-dihydroxyvitamin D.

In yet another aspect, the invention provides a method of reducing therisk of over suppression of plasma iPTH levels in a patient undergoingtreatment for elevated levels of plasma iPTH, or maintenance/preventiontherapy for secondary hyperparathyroidism by administering25-hydroxyvitamin D₃ with or without 25-hydroxyvitamin D₂ and, asnecessary, 1,25-dihydroxyvitamin D₂, so that the blood concentrations of25-hydroxyvitamin D are increased to and maintained at or above 30ng/mL, with 25-hydoxyvitamin D₃ being the predominant hormone, and bloodconcentrations of 1,25-dihydroxyvitamin D are increased to or maintainedwithin a patient's normal historical physiological range for1,25-dihydroxyvitamin D, and elevated plasma iPTH levels are decreasedor controlled while avoiding an abnormally low bone turnover rate.

In another aspect, the invention provides a method of proactivelyadministering 25-hydroxyvitamin D₃ with or without 25-hydroxyvitamin D₂,and/or Vitamin D₃ with or without Vitamin D₂, to an early stage CKDpatient having the potential to develop secondary hyperparathyroidismdue to Vitamin D insufficiency or deficiency.

Given this invention, which is described in more detail herein, itbecomes possible, for the first time, to (1) effectively and safely use25-hydroxyvitamin D₃ with or without 25-hydroxyvitamin D₂, and/orVitamin D₃ with or without Vitamin D₂, to treat secondaryhyperparathyroidism due to Vitamin D insufficiency or deficiency in theearly stages of CKD; (2) concurrently apply these Vitamin D repletiontherapies and Vitamin D hormone replacement therapies for more effectivetreatment of secondary hyperparathyroidism in this population; (3)prevent the recurrence of secondary hyperparathyroidism due to Vitamin Dinsufficiency of deficiency after initial diagnosis and treatment withVitamin D repletion therapies; and (4) prevent the development ofVitamin D insufficiency and deficiency altogether by proactiveadministration of Vitamin D repletion therapy.

A fuller appreciation of the specific attributes of this invention willbe gained upon an examination of the following detailed description ofpreferred embodiments, and the appended claim. Before the embodiments ofthe invention are explained in detail, it is to be understood that theinvention is not limited in its application to the details ofconstruction and the arrangements of the components set forth in thefollowing description. The invention is capable of other embodiments andof being practiced or being carried out in various ways. Also, it isunderstood that the phraseology and terminology used herein are for thepurpose of description and should not be regarded as limiting. The useof “including”, “having” and “comprising” and variations thereof hereinis meant to encompass the items listed thereafter and equivalentsthereof as well as additional items and equivalents thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to treating and preventing secondaryhyperparathyroidism and the underlying chronically low blood levels of1,25-dihydroxyvitamin D by administering safe and effective amounts ofVitamin D repletion therapy with, as necessary, 1,25-dihydrovitamin D₂.It has been discovered that secondary hyperparathyroidism arising in CKDis frequently unresponsive to Vitamin D repletion therapy unless suchtherapy specifically elevates serum total 25-hydroxyvitamin D to levelsof at least 30 ng/mL and consistently maintains such levels in a mannerwhich ensures that the predominant circulating prohormone is25-hydroxyvitamin D₃. Without ensuring the predominance of circulating25-hydroxyvitamin D₃, adequate production of 1,25-dihydroxyvitamin D bythe remaining renal CYP271B is not fully supported, making control ofchronically elevated PTH (or secondary hyperparathyroidism) incompleteor unlikely. Current approaches to administering Vitamin D replacementtherapies to CKD patients overwhelmingly favor or promote the elevationof serum total 25-hydroxyvitamin D in such a manner that25-hydroxyvitamin D₂ becomes the predominant circulating prohormone, dueto its perceived safety advantage.

It has been further found that elevated levels of circulating either25-hydroxyvitamin D₂ or 25-hydroxyvitamin D₄, in the presence of25-hydroxyvitamin D₃, do not strongly support the production of1,25-dihydroxyvitamin D₂ or 1,25-dihydroxyvitamin D₄, respectively, andinstead support the predominant production of other metabolites,including 24,25-dihydroxyvitamin D₂ and 24,25-dihydroxyvitamin D₄.Unlike 1,25-dihydroxyvitamin D₂ or 1,25-dihydroxyvitamin D₄, thesealternative metabolites do not potently inhibit the secretion of PTH bythe parathyroid glands in secondary hyperparathyroidism.

In one aspect the present invention consists of increasing and thenmaintaining blood concentrations of 25-hydroxyvitamin D at or above 30ng/mL, and blood concentrations of 1,25-dihydroxyvitamin D to within apatient's normal historical physiological range for1,25-dihydroxyvitamin D by administering 25-hydroxyvitamin D₃ with orwithout a lesser amount of 25-hydroxyvitamin D₂ and/or Vitamin D₃ withor without a lesser amount of Vitamin D₂. As noted hereinbefore, manycircumstances can lead to chronically low blood levels of1,25-dihydroxyvitamin D, including the development of CKD, living innorthern latitudes and insufficient intake of cholecalciferol and/orergocalciferol. It has been found that chronic treatment of those CKDpatients in need thereof with appropriate, effective and progressivelyadjusted Vitamin D repletion therapy with, as necessary,1,25-dihydroxyvitamin D₂, can provide blood concentrations of25-hydroxyvitamin D consistently at or above 30 ng/mL, with25-hydroxyvitamin D₃ being the predominant circulating hormone, andblood concentrations of 1,25-dihydroxyvitamin D consistently within thepatient's normal historical physiological range, which together canreduce and often normalize elevated plasma PTH levels and subsequentlymaintain reduced or normalized plasma PTH levels.

In another aspect, the invention provides a method of concurrentlylowering or maintaining plasma iPTH levels, increasing or maintainingserum calcium levels, maintaining serum phosphorous levels, increasingor maintaining serum 25-hydroxyvitamin D levels, and increasing ormaintaining serum 1,25-dihydroxyvitamin D levels in a human patient bychronically administering to the patient appropriate, effective andprogressively adjusted amounts of Vitamin D repletion therapy with, asnecessary, one or more Vitamin D hormone replacement therapies. Manydiseases manifest abnormal blood levels of one or more prohormones,hormones and minerals. In CKD, for example, patients may experiencedecreases in serum total 25-hydroxyvitamin D, and/or1,25-dihydroxyvitamin D, increases in plasma iPTH, decreases in serumcalcium and increases in serum phosphorous. Consistent therapeutic and,then, prophylactic treatment in accordance with the present inventionpresents concurrent leveling and/or maintaining of the prohormone,hormone and mineral levels.

In yet another aspect, the invention provides a method of proactivelyadministering 25-hydroxyvitamin D₃ with or without a lesser amount of25-hydroxyvitamin D₂, and/or Vitamin D₃ with or without a lesser amountof Vitamin D₂, to an early stage CKD patient having the potential todevelop secondary hyperparathyroidism due to Vitamin D insufficiency orVitamin D deficiency with the result that blood concentrations of25-hydroxyvitamin D are maintained consistently at or above 30 ng/mL,with 25-hydroxyvitamin D₃ being the predominant circulating hormone, andblood concentrations of 1,25-dihydroxyvitamin D are maintainedconsistently within the patient's normal historical physiological range,and plasma PTH is maintained at reduced or normal levels.

Preferably blood concentrations of 25-hydroxyvitamin D are maintainedconsistently at or above 30 ng/mL, with 25-hydroxyvitamin D₃ being thepredominant circulating hormone, for at least 14 days, at least 1 month,at least 30 days, at least 2 months, at least three months, at least 90days, or at least 6 months. Further preferably, blood concentrations of1,25-dihydroxyvitamin D are maintained consistently within the patient'snormal historical physiological range, and plasma PTH is maintained atreduced or normal levels, for at least 14 days, at least 1 month, atleast 30 days, at least 2 months, at least three months, at least 90days, or at least 6 months.

“Vitamin D insufficiency and deficiency” is generally defined as havingserum 25-hydroxyvitamin D levels below 30 ng/mL (equivalent to about 75nmol/L)

(National Kidney Foundation guidelines, NKF, Am. J. Kidney Dis.42:S1-S202 (2003), incorporated herein by reference).

The term “vitamin D₂ compound” as used herein refers to a precursor,analog or derivative of ergocalciferol, 25-hydroxyvitamin D₂ or1,25-dihydroxyvitamin D₂.

The term “vitamin D₃ compound” as used herein refers to a precursor,analog or derivative of vitamin D₃ (cholecalciferol), 25-hydroxyvitaminD₃, or 1α,25-dihydroxyvitamin D₃, including, 1α-hydroxyvitamin D₃, thatactivates the vitamin D receptor or that can be metabolically convertedin a human to a compound that activates the vitamin D receptor.

As used herein, the term “patient's normal historical physiologicalrange of serum 1,25-dihydroxyvitamin D” refers to the average bloodconcentration range of 1,25-dihydroxyvitamin D of a patient based on atleast two annual or biannual readings of serum 1,25-dihydroxyvitamin Dlevels taken while the kidneys are healthy.

As used herein the term “hypercalcemia” refers to condition in a patientwherein the patient has corrected serum levels of calcium above 10.2mg/dL. Normal corrected serum levels of calcium for a human are betweenabout 8.6 to 10.2 mg/dL.

As used herein the term “hyperphosphatemia” refers to a condition in apatient having normal kidney function, or Stage 1-4 CKD, wherein thepatient has serum phosphorous levels above 4.6 mg/dL. In a patient whohas Stage 5 CKD, hyperphosphatemia occurs when the patient has serumlevels above 5.5 mg/dL. Normal values for serum phosphorous in a humanare 2.4-4.5 mg/dL.

As used herein the term “over suppression of plasma iPTH” refers to acondition in a patient having adequate kidney function, or Stage 1-3CKD, wherein the patient has levels of plasma iPTH below 15 pg/mL. In apatient having Stage 4 CKD, over suppression of plasma iPTH occurs whenthe patient has levels of plasma iPTH below 30 pg/mL. In a patienthaving Stage 5 CKD, over suppression of plasma iPTH occurs when thepatient has levels of plasma iPTH below 150 pg/mL.

As used herein, the term “Vitamin D repletion therapy” refers to theadministration to a patient of an effective amount of a vitamin D₃compound with a vitamin D compound, e.g., cholecalciferol with orwithout a lesser amount of ergocalciferol, and/or 25-hydroxyvitamin D₃with or without a lesser amount of 25-hydroxyvitamin D₂ via any route ofadministration.

As used herein, the term “Vitamin D hormone replacement therapy” refersto the administration to a patient of an effective amount of1,25-dihydroxyvitamin D₂, 1,25-dihydroxyvitamin D₃,1,25-dihydroxyvitamin D₄, or other metabolites and analogs of Vitamin Dwhich can substantially occupy the intracellular VDR.

The term “therapeutically effective amount” depends on the patient'scondition and is an amount effective to achieve a desired clinicaleffect, e.g. to maintain a laboratory test value within the normal rangeor the recommended range for that patient's condition, or an amounteffective to reduce the occurrence or severity of a clinical sign orsymptom of disease. In some embodiments, a therapeutically effectiveamount is an amount effective on average to maintain serum25-hydroxyvitamin D levels or 25-hydroxyvitamin D3 levels at about 30ng/mL (equivalent to about 75 nmol/L) or higher. Such levels may bemaintained for an extended period, for example at least one month, atleast three months, at least six months, nine months, one year, orlonger. In other embodiments, a therapeutically effective amount is anamount effective on average to achieve at least a 15%, 20%, 25% or 30%reduction in serum parathyroid hormone levels (iPTH) from baselinelevels without treatment. In yet other embodiments, a therapeuticallyeffective amount is an amount effective on average to reach CKDstage-specific iPTH target ranges which for Stage 3 is 35-70 pg/mL(equivalent to 3.85-7.7 pmol/L), for Stage 4 is 70-110 pg/mL (equivalentto 7.7-12.1 pmol/L), and for Stage 5 is 150-300 pg/mL (equivalent to16.5-33.0 pmol/L) (defined in K/DOQI Guideline No. 1). When used inreference to an amount of a vitamin D₃ compound, “therapeuticallyeffective” can refer either to the effective amount of vitamin D₃supplement when administered alone, or to the effective amount ofvitamin D₃ compound when administered in combination with a vitamin D₂compound.

It also is specifically understood that any numerical value recitedherein includes all values from the lower value to the upper value,i.e., all possible combinations of numerical values between the lowestvalue and the highest value enumerated are to be considered to beexpressly stated in this application. For example, if a concentrationrange or a beneficial effect range is stated as 1% to 50%, it isintended that values such as 2% to 40%, 10% to 30%, or 1% to 3%, etc.,are expressly enumerated in this specification. These are only examplesof what is specifically intended.

Ergocalciferol, cholecalciferol, 25-hydroxyvitamin D₂ and/or25-hydroxyvitamin D₃, 1,25-dihydroxyvitamin D₂, and analogs thereof areuseful as pharmacologically active compounds of this invention. Thepharmacologically active compounds of this invention can be processed inaccordance with conventional methods of pharmacy to producepharmaceutical agents for administration to patients, e.g., inadmixtures with conventional excipients such as pharmaceuticallyacceptable organic or inorganic carrier substances suitable forparenteral, enteral (e.g., oral), topical or transdermal applicationwhich do not deleteriously react with the active compounds. Suitablepharmaceutically acceptable carriers include, but are not limited to,water, salt (buffer) solutions, alcohols, gum arabic, mineral andvegetable oils, benzyl alcohols, polyethylene glycols, gelatin,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy methylcellulose, polyvinyl pyrrolidone, etc.

The pharmaceutical preparations can be sterilized and, if desired, mixedwith auxiliary agents, e.g., lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, flavoring and/or aromatic active compounds. If apharmaceutically acceptable solid carrier is used, the dosage form ofthe analogs may be tablets, capsules, powders, suppositories, orlozenges. If a liquid carrier is used, soft gelatin capsules,transdermal patches, aerosol sprays, topical creams, syrups or liquidsuspensions, emulsions or solutions may be the dosage form.

For parenteral application, particularly suitable are injectable,sterile solutions, preferably oily or aqueous solutions, as well assuspensions, emulsions, or implants, including suppositories. Ampoulesare convenient unit dosages.

For enteral application, particularly suitable are tablets, dragées,liquids, drops, suppositories, or capsules such as soft gelatincapsules. A syrup, elixir, or the like can be used wherein a sweetenedvehicle is employed.

Sustained or directed release compositions can be formulated, e.g.,liposomes or those wherein the active compound is protected withdifferentially degradable coatings, such as by microencapsulation,multiple coatings, etc. It is also possible to freeze-dry the newcompounds and use the lypolizates obtained, for example, for thepreparation of products for injection. Transdermal delivery ofpharmaceutical compositions of the compounds of the invention is alsopossible.

For topical application, there are employed as nonsprayable forms,viscous to semi-solid or solid forms comprising a carrier compatiblewith topical application and having a dynamic viscosity preferablygreater than water. Suitable formulations include, but are not limitedto, solutions, suspensions, emulsions, creams, ointments, powders,liniments, salves, aerosols, etc., which are, if desired, sterilized ormixed with auxiliary agents, e.g., preservatives, etc.

It is possible, if desired, to produce the metabolites of certain onesof the compounds of the invention, in particular by nonchemical means.For this purpose, it is possible to convert them into a suitable formfor administration together with at least one vehicle or auxiliary and,where appropriate, combined with one or more other active compounds.

The dosage forms may also contain adjuvants, such as preserving orstabilizing adjuvants. They may also contain other therapeuticallyvaluable substances or may contain more than one of the compoundsspecified herein and in the claims in admixture.

As described hereinbefore, Vitamin D repletion and Vitamin D hormonereplacement therapies are preferably administered to the human patientsin oral or intravenous dosage formulations. The administration of suchtherapies, in accordance with the present invention, can be on anepisodic basis, suitably from daily, to 1 to 3 times a week. Suitablythe dosage of Vitamin D replacement therapy or Vitamin D hormonereplacement therapy is about 0.5 μg to about 400 μg per week, dependingon the agent selected. Suitably such therapies can be given in a unitdosage form between about 0.5 μg to about 100 μg, or about 0.5 μg toabout 10 μg in a pharmaceutically acceptable carrier per unit dosage.Episodic doses can be a single dose or, optionally, divided into 2-4subdoses which, if desired, can be given, e.g., twenty minutes to anhour apart until the total dose is given.

Those of ordinary skill in the art will readily optimize effective dosesand co-administration regimens as determined by good medical practiceand the clinical condition of the individual patient. Regardless of themanner of administration, it will be appreciated that the actualpreferred amounts of active compound in a specific case will varyaccording to the efficacy of the specific compound employed, theparticular compositions formulated, the mode of application, and theparticular situs and organism being treated. For example, the specificdose for a particular patient depends on age, sex, body weight, generalstate of health, on diet, on the timing and mode of administration, onthe rate of excretion, and on medicaments used in combination and theseverity of the particular disorder to which the therapy is applied.Dosages for a given patient can be determined using conventionalconsiderations, e.g., by customary comparison of the differentialactivities of the subject compounds and of a known agent, such as bymeans of an appropriate conventional pharmacological protocol. Aphysician of ordinary skill can readily determine and prescribe theeffective amount of the drug required to counter or arrest the progressof the condition. Optimal precision in achieving concentrations of drugwithin the range that yields efficacy without toxicity requires aregimen based on the kinetics of the drug's availability to targetsites. This involves a consideration of the distribution, equilibrium,and elimination of a drug. The dosage of active ingredient in thecompositions of this invention may be varied; however, it is necessarythat the amount of the active ingredient be such that an efficaciousdosage is obtained. The active ingredient is administered to patients(animal and human) in need of treatment in dosages that will provideoptimal pharmaceutical efficacy.

Bulk quantities of Vitamin D and Vitamin D analogs in accordance withthe present invention can be readily obtained in accordance with themany widely known processes.

The compositions, methods and kits of the invention are useful fortreating any subject in need of vitamin D supplementation, eitherprophylactically to prevent vitamin D insufficiency or deficiency, ortherapeutically to replete low serum vitamin 25(OH)D levels to normalrange or above. The compositions and methods of the invention are alsouseful for preventing or treating secondary hyperparathyroidismresulting from low vitamin D levels. In general, serum 25(OH)D valuesless than 5 ng/mL indicate severe deficiency associated with rickets andosteomalacia. Although 30 ng/mL has been suggested as the low end of thenormal range, more recent research suggests that PTH levels and calciumabsorption are not optimized until serum total 25(OH)D levels reachapproximately 40 ng/mL. [See also Vieth, R. Prog Biophys Mol Biol. 2006September; 92(1):26-32.] The term “subject” or “patient” as used hereinincludes humans, mammals (e.g., dogs, cats, rodents, sheep, horses,cows, goats), veterinary animals and zoo animals.

Patients in need of vitamin D supplementation include healthy subjectsand subjects at risk for vitamin D insufficiency or deficiency, forexample, subjects with stage 1, 2, 3, 4 or 5 chronic kidney disease;infants, children and adults that do not drink vitamin D fortified milk(e.g. lactose intolerant subjects, subjects with milk allergy,vegetarians who do not consume milk, and breast fed infants); subjectswith rickets; subjects with dark skin (e.g., in the U.S., 42% of AfricanAmerican women between 15 and 49 years of age were vitamin D deficientcompared to 4% of white women); the elderly (who have a reduced abilityto synthesize vitamin D in skin during exposure to sunlight and also aremore likely to stay indoors); institutionalized adults (who are likelyto stay indoors, including subjects with Alzheimer's disease or mentallyill); subjects who cover all exposed skin (such as members of certainreligions or cultures); subjects who always use sunscreen (e.g., theapplication of sunscreen with an Sun Protection Factor (SPF) of 8reduces production of vitamin D by 95%, and higher SPFs may furtherreduce cutaneous vitamin D production); subjects with fat malabsorptionsyndromes (including but not limited to cystic fibrosis, cholestaticliver disease, other liver disease, gallbladder disease, pancreaticenzyme deficiency, Crohn's disease, inflammatory bowel disease, sprue orceliac disease, or surgical removal of part or all of the stomach and/orintestines); subjects with inflammatory bowel disease; subjects withCrohn's disease; subjects who have had small bowel resections; subjectswith gum disease; subjects taking medications that increase thecatabolism of vitamin D, including phenytoin, fosphenytoin,phenobarbital, carbamazepine, and rifampin; subjects taking medicationsthat reduce absorption of vitamin D, including cholestyramine,colestipol, orlistat, mineral oil, and fat substitutes; subjects takingmedications that inhibit activation of vitamin D, includingketoconazole; subjects taking medications that decrease calciumabsorption, including corticosteroids; subjects with obesity (vitamin Ddeposited in body fat stores is less bioavailable); subjects withosteoporosis and/or postmenopausal women. According to the Institute ofMedicine's report on the Dietary Reference Intakes for vitamin D, foodconsumption data suggest that median intakes of vitamin D for bothyounger and older women are below current recommendations; data suggestthat more than 50% of younger and older women are not consumingrecommended amounts of vitamin D. Optionally excluded from the methodsof the invention are therapeutic treatment of subjects suffering fromrenal osteodystrophy (including osteomalacia and osteitis fibrosacystica).

In other aspects, the compositions and methods of the invention areuseful for prophylactic or therapeutic treatment of vitamin D-responsivediseases, i.e., diseases where vitamin D, 25(OH)D or active vitamin D(e.g., 1,25(OH)₂D) prevents onset or progression of disease, or reducessigns or symptoms of disease. Such vitamin D-responsive diseases includecancer (e.g., breast, lung, skin, melanoma, colon, colorectal, rectal,prostate and bone cancer). 1,25(OH)₂D has been observed to induce celldifferentiation and/or inhibit cell proliferation in vitro for a numberof cells. Vitamin D-responsive diseases also include autoimmunediseases, for example, type I diabetes, multiple sclerosis, rheumatoidarthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave'sdisease, Hashimoto's disease, acute or chronic transplant rejection,acute or chronic graft versus host disease, inflammatory bowel disease,Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome,eczema and psoriasis, dermatitis, including atopic dermatitis, contactdermatitis, allergic dermatitis and/or chronic dermatitis. VitaminD-responsive diseases also include other inflammatory diseases, forexample, asthma, chronic obstructive pulmonary disease, polycystickidney disease (PKD), polycystic ovary syndrome, pancreatitis,nephritis, hepatitis, and/or infection. Vitamin D-responsive diseaseshave also been reported to include hypertension and cardiovasculardiseases. Thus, the invention contemplates prophylactic or therapeutictreatment of subjects at risk of or suffering from cardiovasculardiseases, for example, subjects with atherosclerosis, arteriosclerosis,coronary artery disease, cerebrovascular disease, peripheral vasculardisease, myocardial infarction, myocardial ischemia, cerebral ischemia,stroke, congestive heart failure, cardiomyopathy, obesity or otherweight disorders, lipid disorders (e.g. hyperlipidemia, dyslipidemiaincluding associated diabetic dyslipidemia and mixed dyslipidemiahypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia,and low HDL (high density lipoprotein)), metabolic disorders (e.g.Metabolic Syndrome, Type II diabetes mellitus, Type I diabetes mellitus,hyperinsulinemia, impaired glucose tolerance, insulin resistance,diabetic complication including neuropathy, nephropathy, retinopathy,diabetic foot ulcer and cataracts), and/or thrombosis.

The present invention is further explained by the following examplewhich should not be construed by way of limiting the scope of thepresent invention. The following example demonstrates that theconcomitant administration of Vitamin D repletion and Vitamin D hormonereplacement therapies has improved efficacy in reducing or preventingelevated blood PTH levels as well as maintaining adequate andappropriate levels of serum calcium, serum phosphorous, serum total25-hydroxyvitamin D and serum total 1,25-dihydroxyvitamin D.

EXAMPLE 1 Efficacy Study in Patients With Stage 4 CKD and SecondaryHyperparathyroidism Associated With Vitamin D Insufficiency

The effectiveness of 25-hydroxyvitamin D₃ and, as necessary,1,25-dihydroxyvitamin D₂ in restoring serum total 25-hydroxyvitamin D tooptimal levels (>30 ng/mL) and serum total 1,25-dihydroxyvitamin D toadequate levels (>25 pg/mL) is examined in an open-ended study of adultmale and female patients with Stage 4 CKD and secondaryhyperparathyroidism associated with vitamin D insufficiency. Twoformulations are used in the study. One of the formulations (Formulation#1) is a soft gelatin capsule containing 30 μg of 25-hydroxyvitamin D₃.The second formulation (Formulation #2) is a soft gelatin capsulecontaining 0.25 μg of 1,25-dihydroxyvitamin D₂. A total of 100 subjectsparticipate in this study, all of whom are aged 30 to 70 years and haveserum 25-hydoxyvitamin D levels between 15 and 29 ng/mL (inclusive) andserum intact parathyroid hormone (iPTH) levels above the target levelspublished in the current K/DOQI Guidelines at the time of enrolment. Allsubjects abstain from taking other Vitamin D supplements for 60 daysbefore study start and continuing through study termination, and fromsignificant sun exposure. All subjects begin daily dosing with twocapsules of Formulation #1. Serum total 25-hydroxyvitamin D is measuredat biweekly intervals and serum iPTH is determined at quarterlyintervals. After 1 month, the daily dosage of Formulation #1 ismaintained unchanged in patients whose serum total 25-hydroxyvitamin Dis between 50 and 90 ng/mL, increased by one capsule in patients whoseserum total 25-hydroxyvitamin D is below 50 ng/mL, and decreased by onecapsule per day in patients whose serum total 25-hydroxyvitamin D isabove 90 ng/mL. Further adjustments in the daily dose are made as neededin order to maintain serum total 25-hydroxyvitamin D between 50 and 90ng/mL. After 6 months, subjects whose serum iPTH levels are above K/DOQItargets also begin receiving a daily dose of one capsule of Formulation#2. The dosage of Formulation #2 is adjusted upwards in one capsuleincrements at monthly intervals until serum iPTH levels are loweredprogressively into

K/DOQI targets. Dosing with both Formulation #1 and #2 is continuedindefinitely, provided that hypercalcemia, hypercalciuria andhyperphosphatemia do not develop, in which case appropriate adjustmentsin dosage are made. After 1 year, the subjects' ongoing serum total25-hydroxyvitamin D levels are found to remain stable between 50 and 90ng/mL, serum total 1,25-dihydroxyvitamin D levels are found to remainstable at levels that are within the subjects' normal historical rangeprior to the onset of advanced CKD and serum iPTH is found to remainstable at levels consistent with targets published in the K/DOQIGuidelines. The incidence of hypercalcemia, hypercalciuria andhyperphosphatemia are rare once stable dosing has been achieved.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

Embodiments contemplated in view of the foregoing description includethe following numbered paragraphs.

1. A method of treating and preventing secondary hyperparathyroidism ina patient suffering from chronic kidney disease, comprising increasingor maintaining blood concentrations of both 25-hydroxyvitamin D and1,25-dihydroxyvitamin D in the patient by administering25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂, wherein25-hydroxyvitamin D₃ is the predominant prohormone in circulation.

2. The method of paragraph 1, comprising administering said25-hydroxyvitamin D compounds such that blood concentrations of25-hydroxyvitamin D are increased to and maintained at or above 30ng/mL.

3. The method according to paragraph 1, further comprising administering1,25-dihydroxyvitamin D₂ as a Vitamin D hormone replacement therapy tothe patient.

4. The method of paragraph 3, comprising administering the1,25-dihydroxyvitamin D₂ as such that blood concentrations of serumtotal 1,25-dihydroxyvitamin D₂ are increased to or maintained within apatient's normal historical physiological range for serum total1,25-dihydroxyvitamin D without causing side effects, includinghypercalcemia, hyperphosphatemia, hypercalciuria and oversuppression ofiPTH.

5. A method of concurrently lowering or maintaining plasma iPTH levels,increasing or maintaining serum calcium levels, maintaining serumphosphorous levels, increasing or maintaining serum 25-hydroxyvitamin D,or increasing or maintaining serum 1,25-dihydroxyvitamin D levels in ahuman patient diagnosed with early stage CKD, comprising administeringto the patient, 25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂and, further optionally as necessary, 1,25-dihydroxyvitamin D₂, suchthat the blood concentrations of 25-hydroxyvitamin D in the patient areincreased to and maintained at or above 30 ng/mL, with 25-hydoxyvitaminD₃ being the predominant prohormone, and blood concentrations of1,25-dihydroxyvitamin D are increased to or maintained within apatient's normal historical physiological range for1,25-dihydroxyvitamin D.

6. A method of reducing the risk of over suppression of plasma iPTHlevels in a patient undergoing treatment for elevated levels of plasmaiPTH, or maintenance/prevention therapy for secondaryhyperparathyroidism, comprising administering 25-hydroxyvitamin D₃ andoptionally 25-hydroxyvitamin D₂ and, further optionally as necessary,1,25-dihydroxyvitamin D₂, so that the blood concentrations of25-hydroxyvitamin D are increased to and maintained at or above 30ng/mL, with 25-hydoxyvitamin D₃ being the predominant prohormone, andblood concentrations of 1,25-dihydroxyvitamin D are increased to ormaintained within a patient's normal historical physiological range for1,25-dihydroxyvitamin D, and elevated plasma iPTH levels are decreasedor controlled while avoiding an abnormally low bone turnover rate.

7. A method of treatment, comprising proactively administering25-hydroxyvitamin D₃ and/or Vitamin D₃, optionally concurrently withadministration of 25-hydroxyvitamin D₂, and/or Vitamin D₂, to an earlystage CKD patient having the potential to develop secondaryhyperparathyroidism due to Vitamin D insufficiency or deficiency.

8. A method according to paragraph 4, comprising administering said25-hydroxyvitamin D₃ to increase blood concentration of25-hydroxyvitamin D in the patient to a level of at least 30 ng/mL.

9. The method according to paragraph 8, further comprising administeringsaid 25-hydroxyvitamin D₃ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 30 days.

10. The method according to paragraph 9, comprising administering said25-hydroxyvitamin D₃ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 90 days.

11. The method according to paragraph 2, further comprisingadministering said 25-hydroxyvitamin D₃ to maintain blood concentrationof 25-hydroxyvitamin D in the patient at a level of at least 30 ng/mLfor at least 30 days.

12. The method according to paragraph 11, comprising administering said25-hydroxyvitamin D₃ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 90 days.

13. The method according to paragraph 5, further comprisingadministering said 25-hydroxyvitamin D₃ to maintain blood concentrationof 25-hydroxyvitamin D in the patient at a level of at least 30 ng/mLfor at least 30 days.

14. The method according to paragraph 13, comprising administering said25-hydroxyvitamin D₃ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 90 days.

15. The method according to paragraph 6, further comprisingadministering said 25-hydroxyvitamin D₃ to maintain blood concentrationof 25-hydroxyvitamin D in the patient at a level of at least 30 ng/mLfor at least 30 days.

16. The method according to paragraph 15, comprising administering said25-hydroxyvitamin D₃ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 90 days.

17. A method according to paragraph 7, comprising administering said25-hydroxyvitamin D₃ to increase blood concentration of25-hydroxyvitamin D in the patient to a level of at least 30 ng/mL.

18. The method according to paragraph 17, further comprisingadministering said 25-hydroxyvitamin D₃ to maintain blood concentrationof 25-hydroxyvitamin D in the patient at a level of at least 30 ng/mLfor at least 30 days.

19. The method according to paragraph 18, comprising administering said25-hydroxyvitamin D₃ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 90 days.

20. The method according to paragraph 7, comprising administering25-hydroxyvitamin D₃ such that 25-hydroxyvitamin D₃ is the predominantprohormone in circulation.

What is claimed is:
 1. A method of treating secondaryhyperparathyroidism in a patient suffering from chronic kidney diseaseStage 3 or Stage 4, comprising administering to the patient an effectiveamount of 25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂ toreduce the patient's serum parathyroid hormone level while safelyraising or maintaining both serum total 25-hydroxyvitamin D and serumtotal 1,25-dihydroxyvitamin D, wherein serum 25-hydroxyvitamin D₃ isgreater than serum 25-hydroxyvitamin D₂ or serum 25-hydroxyvitamin D₄,and wherein said 25-hydroxyvitamin D₂, when administered, isadministered in a lesser amount than said 25-hydroxyvitamin D₃.
 2. Themethod of claim 1, comprising administering said 25-hydroxyvitamin D₃and optionally 25-hydroxyvitamin D₂ such that blood concentrations of25-hydroxyvitamin D are increased to and maintained at or above 30ng/mL.
 3. The method of claim 1, further comprising administering1,25-dihydroxyvitamin D₂ as a Vitamin D hormone replacement therapy tothe patient.
 4. The method of claim 1, comprising administering said25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂ such that bloodconcentrations of serum total 1,25-dihydroxyvitamin D are increased toor maintained within a patient's normal historical physiological rangefor serum total 1,25-dihydroxyvitamin D without causing side effectsselected from the group consisting of hypercalcemia, hyperphosphatemia,hypercalciuria and oversuppression of iPTH.
 5. The method of claim 2,further comprising administering said 25-hydroxyvitamin D₃ andoptionally 25-hydroxyvitamin D₂ to maintain blood concentration of25-hydroxyvitamin D in the patient at a level of at least 30 ng/mL forat least 30 days.
 6. The method of claim 5, comprising administeringsaid 25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂ tomaintain blood concentration of 25-hydroxyvitamin D in the patient at alevel of at least 30 ng/mL for at least 90 days.
 7. The method of claim1, wherein the patient's serum parathyroid hormone level is reduced byat least 30%.
 8. The method of claim 1, wherein the patient is vitamin Dinsufficient or vitamin D deficient.
 9. The method of claim 1, whereinthe patient's serum parathyroid hormone level is reduced to the targetrange for the CKD Stage.
 10. The method of claim 4, wherein said amountof 25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂ is furthereffective to maintain serum total 1,25-dihydroxyvitamin D within thepatient's normal historical physiological range for at least 30 days.11. The method of claim 1, wherein said amount of 25-hydroxyvitamin D₃and optionally 25-hydroxyvitamin D₂ is further effective to maintain thepatient's serum parathyroid hormone level at a reduced level frombaseline level for at least 30 days.
 12. The method of claim 1, whereinsaid amount of 25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂is further effective to concurrently maintain plasma PTH at a reducedlevel from baseline level, blood concentration of 25-hydroxyvitamin D ata level of at least 30 ng/mL, and blood concentration of1,25-dihydroxyvitamin D within the patient's normal historicalphysiological range for at least 30 days.
 13. A method of treatingsecondary hyperparathyroidism in a patient suffering from chronic kidneydisease Stage 3 or Stage 4, comprising administering to the patient aneffective amount of 25-hydroxyvitamin D₃ and optionally25-hydroxyvitamin D₂ to reduce the patient's serum parathyroid hormonelevel while safely raising or maintaining both serum total25-hydroxyvitamin D and serum total 1,25-dihydroxyvitamin D, whereinserum total 25-hydroxyvitamin D is increased to and/or maintained in arange of 30 ng/mL to 90 ng/mL, wherein serum 25-hydroxyvitamin D₃ isgreater than serum 25-hydroxyvitamin D₂ or serum 25-hydroxyvitamin D₄,and wherein said 25-hydroxyvitamin D₂, when administered, isadministered in a lesser amount than said 25-hydroxyvitamin D₃.
 14. Themethod according to claim 13, further comprising administering1,25-dihydroxyvitamin D₂ as a Vitamin D hormone replacement therapy tothe patient.
 15. The method of claim 13, comprising administering said25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂ such that bloodconcentrations of serum total 1,25-dihydroxyvitamin D are increased toor maintained within a patient's normal historical physiological rangefor serum total 1,25-dihydroxyvitamin D without causing side effectsselected from the group consisting of hypercalcemia, hyperphosphatemia,hypercalciuria and oversuppression of iPTH.
 16. The method of claim 13,further comprising administering said 25-hydroxyvitamin D₃ andoptionally 25-hydroxyvitamin D₂ to increase and/or maintain bloodconcentration of 25-hydroxyvitamin D in the patient in a range of 30ng/mL to 90 ng/mL for at least 30 days.
 17. The method of claim 13,wherein the patient's serum parathyroid hormone level is reduced by atleast 30%.
 18. The method of claim 13, wherein the patient is vitamin Dinsufficient or vitamin D deficient.
 19. The method of claim 13, whereinthe patient's serum parathyroid hormone level is reduced to the targetrange for the CKD Stage.
 20. The method of claim 13, wherein said amountof 25-hydroxyvitamin D₃ and optionally 25-hydroxyvitamin D₂ is furthereffective to maintain the patient's serum parathyroid hormone level at areduced level from baseline level for at least 30 days.